- Title
- Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1
- Creator
- Shahbazi, Jeyran; Scarlett, Christopher J.; Lock, Richard B.; Liu, Tao; Norris, Murray D.; Liu, Bing; Haber, Michelle; Tee, Andrew E.; Carrier, Alice; Biankin, Aandrew V.; London, Wendy B.; Marshall, Glenn M.
- Relation
- Oncotarget Vol. 5, Issue 12, p. 4257-4268
- Publisher Link
- http://dx.doi.org/10.18632/oncotarget.1991
- Publisher
- Impact Journals LLC
- Resource Type
- journal article
- Date
- 2014
- Description
- Myc oncoproteins and histone deacetylases (HDACs) exert oncogenic effects by modulating gene transcription. Paradoxically, N-Myc induces p53 gene expression. Tumor protein 53-induced nuclear protein 1 (TP53INP1) phosphorylates p53 protein at serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes and programmed cell death. Here we aimed to identify the mechanism through which N-Myc overexpressing p53 wild-type neuroblastoma cells acquired resistance to apoptosis. TP53INP1 was found to be one of the genes most significantly repressed by HDAC2 and N-Myc according to Affymetrix microarray gene expression datasets. HDAC2 and N-Myc reduced TP53INP1 gene expression by direct binding to the TP53INP1 gene promoter, leading to transcriptional repression of TP53INP1, p53 protein de-phosphorylation at serine 46, neuroblastoma cell proliferation and survival. Moreover, low levels of TP53INP1 expression in human neuroblastoma tissues correlated with high levels of N-Myc expression and poor patient outcome, and the BET bromodomain inhibitors JQ1 and I-BET151 reduced N-Myc expression and reactivated TP53INP1 expression in neuroblastoma cells. These findings identify TP53INP1 repression as an important co-factor for N-Myc oncogenesis, and provide further evidence for the potential application of BET bromodomain inhibitors in the therapy of N-Myc-induced neuroblastoma.
- Subject
- N-Myc; HDAC2; p53; TP53INP1
- Identifier
- http://hdl.handle.net/1959.13/1304408
- Identifier
- uon:20844
- Identifier
- ISSN:1949-2553
- Language
- eng
- Full Text
- Reviewed
- Hits: 11858
- Visitors: 11960
- Downloads: 227
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT02 | Publisher version (open access) | 5 MB | Adobe Acrobat PDF | View Details Download |